Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[C:14]([NH:16][CH2:17][C:18]2[CH:28]=[CH:27][C:21]([C:22](OCC)=[O:23])=[CH:20][CH:19]=2)=[O:15])=[CH:9][CH:8]=1.O>CO.C(O)(=O)C>[F:6][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[CH:29][C:30]2[CH:35]=[C:34]([O:36][CH3:37])[C:33]([O:38][CH3:39])=[C:32]([O:40][CH3:41])[CH:31]=2)[C:14]([NH:16][CH2:17][C:18]2[CH:28]=[CH:27][C:21]([C:22]([NH:2][OH:3])=[O:23])=[CH:20][CH:19]=2)=[O:15])=[CH:11][CH:12]=1
Reactant: NO
Reactant: CCOC(=O)c1ccc(CNC(=O)C(=Cc2cc(OC)c(OC)c(OC)c2)c2ccc(F)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C=C(C(=O)NCc2ccc(C(=O)NO)cc2)c2ccc(F)cc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.9 %

Procedure:
Hydroxylamine hydrochloride (1.25 g, 18 mmol) in methanol (3 mL) was mixed with KOH (1.0 g, 18 mmol) in methanol (6 mL) at 0° C. and the reaction mixture was sonicated for 5 minutes. A white precipitate was formed which was filtered. The filtrate was immediately added to the ethyl 4-((2-(4-fluorophenyl)-3-(3,4,5-trimethoxyphenyl)acrylamido)methyl)benzoate (0.4 g, 1 mmol) followed by the addition of KOH (0.084 g, 1.5 mmol) and the mixture was stirred at room temperature for 1 hour. Around 20 mL of water was added to the reaction mixture and it was neutralized to pH 7 by addition of dilute acetic acid. Upon standing, a colorless precipitate was formed, it was filtered, dried and triturated with dichloromethane/hexanes (1:1, 20 mL), to afford the required compound as a pure colorless solid (0.254 g, 38% yield). 1H NMR (DMSO-d6) δ (ppm): 3.49 (61-1, s, —OCH3), 3.60 (3H, s, —OCH3), 4.36 (2H, d, —CH2), 6.32 (2H, s, Ar—H), 7.29-7.39 (6H, d, Ar—H), 7.48 (1H, s, ═CH), 7.69 (2H, d, Ar—H), 7.96 (1H, t, —NH), 8.99 (1H, s, —OH), 11.16 (1H, s, —NH); MS m/z: 497.1 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[H-].[Na+].CC1C=CC(S(O[CH:37]2[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38]2)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O.CO>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[CH:13][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[CH:9][N:8]([CH:41]3[CH2:37][CH2:38][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:40]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2[nH]cc(-c3ccc(Oc4ccccc4)cc3)c12
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a solution of 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidine (2.0 g, 6.6 mmol) in dry DMF (120 ml) under nitrogen at 0° C. was added NaH (0.264 g, 60% dispeersion, 6.6 mmol) and then reaction mixture warmed to room temperature and stirred for 1 hr. tert-butyl 3-[(4-methylphenyl)sulfonyl]oxy-1-pyrrolidinecarboxylate (2.25 g, 6.6 mmol) was added portionwise and the mixture heated at 95° C. for 72 hr. Quench with water and extract with EtOAc (4×100 ml). Wash the combined organic solutions with water (4×100 ml) and brine (2×100 ml). The organics were dried (sodium sulphate), filtered and evaporated to leave a solid which was dissolved in EtOAc/MeOH and adsorbed onto silica. Purification using flash silica gel column chromatography with 5% MeOH/EtOAc as eluent gave in F 17-25 tert-butyl 3-[4-amino-5-(4-phenoxyphenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]-1-pyrrolidinecarboxylate (1.0 g, 32%) as a white solid m.pt. 168-170° C. Rf in 9:1 EtOAc: MeOH=0.46. 1H NMR (d6 DMSO, 250 MHz): 8.17 (1H, s), 7.38-7.50 (5H, m), 6.19 (2H, bs), 5.31 (1H, m), 3.77 (1H, m), 3.42-3.60 (3H, m), 2.38 (2H, m), 1.40 (9H, s). Mass spec. 471.2250 (C27H29O3N5) IR (KBr disc): 3130, 1683, 1585, 1404, 1245 cm−1.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[O:9])[CH:3]=1.[Cl:18][S:19](O)(=[O:21])=[O:20]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:19]([Cl:18])(=[O:21])=[O:20])=[CH:13][C:12]=2[CH3:17])=[O:9])[CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: Cc1ccccc1NC(=O)c1cc(Cl)ncn1
Solvent: ClCCl
Product: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A cooled (0° C.) solution of 6-chloro-N-(2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 18; 14.00 g; 56.52 mmol) in DCM (280 ml) was treated dropwise with a solution of chlorosulfonic acid (37.8 ml; 565 mmol) in DCM (100 mL). The reaction mixture was allowed to warm from 0° C. to room temperature, then it was stirred at room temperature overnight. The mixture was cooled to 15° C., a mixture ice/water was added and it was stirred for a few minutes. Phases were separated and the organic layer was washed with cold water, brine, dried over MgSO4, filtered and concentrated under vacuum to afford the title compound as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12]P(=O)(OC)OC)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[Li+].CC([N-]C(C)C)C.[C:33]([N:40]1[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:12]=[C:43]3[CH2:44][CH2:45][N:40]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:41][CH2:42]3)[N:8]2[CH3:11])=[C:4]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COP(=O)(Cc1nc2c(N3CCOCC3)nc(Cl)nc2n1C)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1c(C=C2CCN(C(=O)OC(C)(C)C)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a cold (−78° C.) suspension of dimethyl (2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methylphosphonate (0.35 g, 0.93 mmol) in THF (8.0 mL) was added a 2.0M solution of LDA in THF (0.49 mL). The resulting solution was allowed to warm to room temperature before the addition of a solution of 1-Boc-4-piperidone (0.19 g, 0.95 mmol) in THF (3 mL). The reaction mixture was then stirred at room temperature for 2 hours, and partitioned between brine and DCM. The organic layer was isolated, washed with brine, dried over MgSO4 and concentrated. The crude residue was then purified by flash chromatrography (0-75% EtOAc in heptane) to give the title compound (0.38 g, 91%). LCMS m/z: 449.2 (MH+).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:33])([CH3:32])[C:8]1N=[CH:10][N:11](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[C:34]([C:36]1[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=1[CH2:38]Br)#[N:35].C([NH:46]CC)C.CO>C(#N)C>[C:1]([SiH2:5][O:6][C:7]([CH3:33])([CH3:32])[C:8]1[N:35]([CH2:34][C:36]2[CH:43]=[CH:42][CH:41]=[CH:40][C:37]=2[C:38]#[N:46])[CH:10]=[N:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNCC
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CO
Solvent: CC#N
Product: CC(C)(C)[SiH2]OC(C)(C)c1cncn1Cc1ccccc1C#N
Reaction time: 0.5 h

Procedure:
4-(tert-Butyl-dimethyl-silanyloxymethyl)-1-trityl-1H-imidazole (11.1 g, 24.4 mmol) and 2-cyanobenzyl bromide (5.02 g, 25.62 mmol) in acetonitrile (100 mL) are heated to 60° C. overnight, whereupon diethylamine (30 mL) is added. After 30 min, methanol (2 mL) is added. After 30 min the volatiles are removed in vacuo. The residue is taken up in dichloromethane and washed with water. The organic layer is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel flash chromatography (elution with dichloromethane-methanol, 49:1) to yield partially purified 2-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-ylmethyl]-benzonitrile which is used in the next step without further purification; MS (ESI) m/z 328.2 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2].[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][N:17]=2)[CH2:6][C@@H:5]1[CH3:24])(=[O:3])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(C#C[Si](C)(C)C)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 90 °C

Procedure:
6-(((2S,4R)-1-Acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 6) (1.62 g, 4.20 mmol), ethynyltrimethylsilane (17.5 ml, 124 mmol), triethylamine (23 ml, 165 mmol), bis(triphenylphosphine)palladium(II) chloride (0.590 g, 0.841 mmol) and copper(I) iodide (0.080 g, 0.420 mmol) were mixed in DMF (18 ml) and heated at 90° C. overnight. The reaction was concentrated in vacuo, diluted with water (30 ml), and extracted with DCM (3×30 ml). The organics were combined and dried (hydrophobic frit). The solution was concentrated in vacuo, and the residue purified by chromatography on a silica cartridge (100 g) eluting with an ethylacetate/cyclohexane gradient (0-75% over 14 CVs). The appropriate fractions were collected and the solvent evaporated in vacuo to give 6-(((2S,4R)-1-acetyl-2-methyl-6-((trimethylsilyl)ethynyl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (881 mg) as a black foam, which was used without further purification. LCMS (formate), Rt 1.24 min, MH+ 402
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][O:10]C(=O)C)=[N:7][CH:8]=1)#[N:2].[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C>[OH:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: CC(=O)OCc1ccc(C#N)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccc(CO)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 31A (180 mg, 1.02 mmol) is dissolved in tetrahydrofuran (8 ml). Lithium hydroxide (48.94 mg, 2.04 mmol) is dissolved in water (5 ml) and added to the THF solution. The reaction is stirred for 2 hours at room temperature. The mixture is diluted with water and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate. The organic phases are combined and washed with brine, dried with magnesium sulphate monohydrate, filtered and concentrated in vacuo. The residue is used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[O:6].I[CH3:15]>[Ag]=O.C(#N)C>[Br:1][C:2]1[C:3]([O:13][CH3:15])=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cc([N+](=O)[O-])cc(Br)c1O
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COc1c(Br)cc([N+](=O)[O-])cc1C=O
Temperature: 50 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
Into an appropriately sized pressure bottle was placed commercially available 3-bromo-2-hydroxy-5-nitrobenzaldehyde (2.46 gm, 10.00 mmol), iodomethane (6.23 mL, 100 mmol), silver oxide (2.317 g, 10.00 mmol) and acetonitrile (50 mL). The bottle was sealed and heated with stirring at 50° C. for 2 h. The reaction mixture was filtered through celite and the filtrate concentrated to give a solid residue that was triturated with hexane, collected by filtration and dried. The resulting solid was purified by silica gel chromatography (hexane-ethylacetate) to give the title compound (1.2 g, 46%).
Reaction SMILES: [S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O-:4])(=[O:3])=[O:2].F[C:13]1C=C[C:16]2C(C3CCNCC3)=N[O:19][C:15]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[S:1]([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)([O:4][CH2:13][CH2:14][CH:15]([OH:19])[CH3:16])(=[O:3])=[O:2]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCCC(C)O)cc1
Temperature: 25 °C

Procedure:
Racemic 3-hydroxybutyl tosylate was prepared in a manner described by Ferreira et al., Tetrahedron, 46, pp. 6311-6318, (1990). To a solution of the racemic tosylate (9.2 g, 37.7 mmol) in acetonitrile (190 ml) was added 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (8.3 g, 37.7 mmol) followed by milled potassium carbonate (7.8 g, 56.6 mmol) at room temperature under nitrogen. The reaction mixture was warmed to reflux for 4.5 hours and allowed to cool to room temperature. The solids were removed via filtration through a pad of Celite and were washed with EtOAc. The combined filtrates were concentrated to give the crude product. Purification via preparative HPLC (silica gel, 10% MeOH/EtOAc) afforded 6.3 g (57%), m.p.=100°-102° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:5][CH2:6]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(-c2ncnc3c(C(=O)NC4CCNCC4)c[nH]c23)c(OCC2CC2)c1
Product: CCOC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A152) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3][OH:4].C(NC(C)C)(C)C.[Li].[N:14]1([C:19]2[C:28]3[C:23](=[N:24][C:25](Cl)=[C:26]([Cl:29])[N:27]=3)[N:22]=[C:21](Cl)[N:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1.[NH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>O1CCCC1.O>[Cl:29][C:26]1[N:27]=[C:28]2[C:23](=[N:24][C:25]=1[O:4][CH2:3][CH:2]([F:5])[F:1])[N:22]=[C:21]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)[N:20]=[C:19]2[N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: OCC(F)F
Reactant: C1CNCCN1
Reactant: Clc1nc(N2CCCC2)c2nc(Cl)c(Cl)nc2n1
Agent: [Li]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: FC(F)COc1nc2nc(N3CCNCC3)nc(N3CCCC3)c2nc1Cl
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
a)+b) 50 μl (0.82 mmol) 2,2-difluorethanol are dissolved in 12 ml of tetrahydrofuran and under protective gas combined with 410 μl (0.82 mmol) of a 2 molar solution of lithium diisopropylamine in tetrahydrofuran. The mixture is stirred for 30 minutes and then the mixture is added to a solution of 250 mg (0.82 mmol) 4-pyrrolidin-1-yl-2,6,7-trichloro-pteridine in 12 ml of tetrahydrofuran cooled to −10° C. The mixture is stirred for one hour at −10° C., slowly allowed to come up to ambient temperature and stirred for another four hours. The solvent is eliminated in vacuo, the residue is combined with 50 ml of water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. The residue is taken up in 15 ml of tetrahydrofuran and combined with a solution of 313 mg (3.6 mmol) piperazine in 10 ml of tetrahydrofuran. The mixture is refluxed for approx. 16 hours, cooled to ambient temperature and the solvent is eliminated in vacuo. The residue is mixed with water and extracted with dichloromethane. The organic phase is dried on sodium sulphate and the solvent is eliminated in vacuo. Diisopropylether is added and a yellowish solid is obtained. Yield 225 mg (70% of theoretical)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[CH:12][N:13]=[CH:14]3)=[CH:9][C:8]=2[OH:17])[CH:2]=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][CH:20]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:30][O:29][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][C:25]=1[O:31][CH3:32])[N:22]=[CH:21][CH:20]=[C:19]2[O:17][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:7]=1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:14]=[N:13][CH:12]=[CH:11]2
Reactant: Oc1cc2ccncc2cc1-c1cccnc1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3cc4ccncc4cc3-c3cccnc3)c2cc1OC
Temperature: 140 °C
Reaction time: 4 h
Yield: 54.3 %

Procedure:
7-Pyridin-3-yl-isoquinolin-6-ol (7 mg), 4-chloro-6,7-dimethoxyquinoline (21 mg), and 4-dimethylaminopyridine (12 mg) were suspended in o-dichlorobenzene (1.5 ml), and the suspension was stirred at 140° C. for 4 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (7 mg, yield 55%).
Reaction SMILES: C1C=C[NH+]=CC=1.[O-:7][Cr](Cl)(=O)=O.[CH3:12][S:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2(O)[CH2:24][CH2:23][CH:22]=[C:21]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>C(Cl)Cl.CCOCC>[F:31][C:28]1[CH:29]=[CH:30][C:25]([C:21]2[C:22](=[O:7])[CH2:23][CH2:24][C:20]=2[C:17]2[CH:18]=[CH:19][C:14]([S:13][CH3:12])=[CH:15][CH:16]=2)=[CH:26][CH:27]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CSc1ccc(C2(O)CCC=C2c2ccc(F)cc2)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CSc1ccc(C2=C(c3ccc(F)cc3)C(=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a suspension of PCC (4.5 g, 20.9 mmol) and 10 g of anhydrous 4 Å molecular sieves in 150 mL of CH2Cl2 was added a solution of 2.2 g (7.3 mmol) of 1-(4-(methylthio)phenyl)-2-(4-fluorophenyl)-2-cyclopenten-1-ol in 20 mL CH2Cl2. The mixture was stirred for 1 h at r.t. and then diluted with 300 mL of Et2O. After filtration and concentration, the residue was flash chromatographed with 2:1 hexane/EtOAc to give 1.5 g of the title product. 1H NMR (CDCl3) d 2.45 (3H, s), 2.68 (2H, m), 3.00 (2H, m), 7.02 (2H, J=8.6 Hz, t), 7.11 (2H, J=8.6 Hz, d), 7.15-7.23 (4H, m).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:12]2[O:11][C:10]([CH3:14])([CH3:13])[CH2:9][C:8]=2[C:7]([C:15]2[C:16]([CH3:28])([CH3:27])[C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[N:19]=2)=[CH:6][CH:5]=1.[CH3:29][C:30]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:31]=1[C:32](O)=[O:33]>>[CH3:29][C:30]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:31]=1[C:32]([N:23]1[CH2:24][CH2:25][CH:20]([N:18]2[C:17](=[O:26])[C:16]([CH3:28])([CH3:27])[C:15]([C:7]3[C:8]4[CH2:9][C:10]([CH3:14])([CH3:13])[O:11][C:12]=4[C:4]([O:3][CH3:2])=[CH:5][CH:6]=3)=[N:19]2)[CH2:21][CH2:22]1)=[O:33]
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)c2c1OC(C)(C)C2
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cc(C)ccc4C)CC3)C(=O)C2(C)C)c2c1OC(C)(C)C2

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(7-methoxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-4-yl)-4,4-dimethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B5) and 2,5-dimethylbenzoic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[O:8])[NH:4][N:3]=1.O1CCOCC1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][CH2:39][Cl:40])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.ClCCl>CC(N(C)C)=O.Cl>[Cl:40][CH2:39][CH2:38][CH2:37][O:36][C:30]1[CH:29]=[C:28]2[C:33]([C:24]([NH:1][C:2]3[CH:6]=[C:5]([C:7]([NH:9][C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=4)=[O:8])[NH:4][N:3]=3)=[N:25][CH:26]=[N:27]2)=[CH:32][C:31]=1[O:34][CH3:35]
Reactant: Nc1cc(C(=O)Nc2cccc(F)c2)[nH]n1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCl
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc2c(Nc3cc(C(=O)Nc4cccc(F)c4)[nH]n3)ncnc2cc1OCCCCl
Yield: 88 %

Procedure:
3-Amino-N-(3-fluorophenyl)-1H-pyrazole-5-carboxamide (153 mg, 0.69 mmol) in dimethylacetamide (1.8 ml) and HCl in dioxane (4 M solution in dioxane, 174 μl, 0.69 mmol) was reacted with 4-chloro-7-(3-chloropropoxy)-6-methoxyquinazoline (200 mg, 0.69 mmol) at 90° C. for 1.5 hour. Dichloromethane (35 ml) was added to the cooled reaction mixture, and the solid recovered by filtration, washed with dichloromethane and dried to yield 3-{[7-(3-chloropropoxy)-6-methoxyquinazolin-4-yl]amino}-N-(3-fluorophenyl)-1H-pyrazole-5-carboxamide (286 mg, 81% yield):
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1B1OC(C)(C)C(C)(C)O1>CN(C=O)C.O.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][C:22]1[CH:23]=[C:24]([N:37]2[CH2:41][C@H:40]([CH2:42][NH:43][C:44](=[O:46])[CH3:45])[O:39][C:38]2=[O:47])[CH:25]=[CH:26][C:27]=1[C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH2:12][C@@H:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)C(=O)O1
Reactant: OC[C@@H]1CC(c2ccc(Br)cn2)=NO1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccc(C4=NO[C@H](CO)C4)nc3)c(F)c2)C(=O)O1
Temperature: 75 °C
Yield: 48.7 %

Procedure:
[(5S)-3-(5-Bromopyridin-2-yl)-4,5-dihydroisoxazol-5-yl]methanol (Intermediate 11, 0.5 g, 1.95 mmol), potassium carbonate (0.622 g, 4.5 mmol), N-({(5S)-3-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (Intermediate 13, 0.736 g, 1.95 mmol) and tetrakis(triphenylphosphino)palladium(0) (0.225 g, 0.195 mmol) were combined and suspended in DMF (7 ml) and water (1 ml). The mixture was heated at 75° C. for 2 hours, then was poured into cold water (30 ml). The solids formed were collected, rinsed with water and washed with dichloromethane, dried under vaccuum and collected to give the title compound (0.407 g).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[C:14]([Cl:22])[C:13]=1[NH2:23]>>[Cl:22][C:14]1[CH:15]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:17]=[C:12]2[C:13]=1[NH:23][C:2](=[O:4])[C:1](=[O:8])[NH:11]2
Reactant: Nc1cc(C(F)(F)F)cc(Cl)c1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(C(F)(F)F)cc(Cl)c2[nH]c1=O
Temperature: 180 °C
Reaction time: 3.5 h
Yield: 50.9 %

Procedure:
439.0 mg (3.0 mmol) of diethyl oxalate (from Sigma, used as received) was added to 210.6 mg (1.0 mmol) of 1,2-diamino-3-chloro-5-trifluoromethylbenzene (from PCR Inc., used as received), and the resulting yellow solution was heated at 180° C. (bath temperature) under Ar with stirring for 3.5 h, the solution became thick With formation of cream precipitate and hard to stir. The reaction mixture was allowed to cool to r.t., and triturated with hexane (10 mL). The precipitate was collected by vacuum filtration, washed with hexane (2×10mL) (the combined hexane filtrate was saved), dried under 0.1 mmHg for 4 h affording 134.6 mg (58%) of the crude desired product as a yellow powder (95-98% pure by NMR), mp.330°-2° C. (dec.) (preheated block).